A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion

Abstract

Endogenous retroviruses are cellular genes of retroviral origin captured by their host during the course of evolution and represent around 8% of the human genome. Although most are defective and transcriptionally silenced, some are still able to generate retroviral-like particles and proteins. Among these, the HERV-K(HML2) family is remarkable since its members have amplified relatively recently and many of them still have full length coding genes. Furthermore, they are induced in cancers, especially in melanoma, breast cancer and germ cell tumours, where viral particles, as well as the envelope protein (Env), can be detected. Here we show that HERV-K(HML2) Env per se has oncogenic properties. Its expression in a non-tumourigenic human breast epithelial cell line induces epithelial to mesenchymal transition (EMT), often associated with tumour aggressiveness and metastasis. In our model, this is typified by key modifications in a set of molecular markers, changes in cell morphology and enhanced cell motility. Remarkably, microarrays performed in 293T cells reveal that HERV-K(HML2) Env is a strong inducer of several transcription factors, namely ETV4, ETV5 and EGR1, which are downstream effectors of the MAPK ERK1/2 and are associated with cellular transformation. We demonstrate that HERV-K(HML2) Env effectively activates the ERK1/2 pathway in our experimental setting and that this activation depends on the Env cytoplasmic tail. In addition, this phenomenon is very specific, being absent with every other retroviral Env tested, except for Jaagsiekte Sheep Retrovirus (JSRV) Env, which is already known to have transforming properties in vivo. Though HERV-K Env is not directly transforming by itself, the newly discovered properties of this protein may contribute to oncogenesis.

Expressional activation and functional roles of human endogenous retroviruses in cancers

“…53 An in vitro experiment showed that HERV-K env protein effectively activated the ERK1/2 pathway and induced epithelialmesenchymal transition in a nontumorigenic human breast epithelial cell line, suggesting that this HERV-K env protein has oncogenic properties. 54 Moreover, HERV-K expression was significantly associated with poor outcome in hepatocellular carcinoma patients, 55 as well as cancer progression in soft tissue sarcoma. 56 Elevated HERV-K gag expression in PBMC was associated with prostate cancer diagnosis particularly in older men and smokers who tend to develop a more aggressive disease.…”

“…Furthermore, HERV‐K antibodies and mRNA are elevated in blood of patients at an early stage of breast cancer and further increased in patients who are at risk of developing metastatis . An in vitro experiment showed that HERV‐K env protein effectively activated the ERK1/2 pathway and induced epithelial‐mesenchymal transition in a nontumorigenic human breast epithelial cell line, suggesting that this HERV‐K env protein has oncogenic properties . Moreover, HERV‐K expression was significantly associated with poor outcome in hepatocellular carcinoma patients, as well as cancer progression in soft tissue sarcoma .…”

Capture of a Hyena-Specific Retroviral Envelope Gene with Placental Expression Associated in Evolution with the Unique Emergence among Carnivorans of Hemochorial Placentation in Hyaenidae

“…The latter differs from the former mainly by the disruption of maternal blood vessel walls by invading fetal cells, resulting in maternal blood bathing the syncytial maternofetal interface, as observed in all hemochorial placentas, including human placenta (19). In this respect it is worth mentioning that a recent analysis of the properties of the envelope protein of the human endogenous retrovirus K (HERV-K) family of human endogenous retroviruses has provided hints that this envelope could promote an epithelial-mesenchymal phenotypic transition (EMT) as well as cellular invasion (38) and that the recently described syncytin-Mab1 seems able to modulate cell migration phenomena through interaction with its cognate receptor (16). Although preliminary assays carried out with Hyena-Env2 could not demonstrate a similar effect, a more refined experimental setup, or even better, identification of the Hyena-Env2 receptor, should now be carried out to understand in molecular terms how the captured envelope can contribute to the transition in placentation type.…”

Does HERV-K represent a potential therapeutic target for prostate cancer?

“…Likewise, despite their obvious upregulation during prostate cancer progression, no direct oncogenic effects of Gag proteins or transcripts have been reported. Targeting HERV-K Env proteins by antibodies may interfere with the proliferation of cancer cells [15]. However, HERV-K Env expression in prostate cancer is apparently limited and has not yet been demonstrated to promote cancer growth.…”

“…HERV-K Rec proteins may also bind specific RNAs and affect their translation [14], but this mechanism has not been studied in prostate cancer. In cells from other cancers, certain Env proteins are proposed to modulate signal transduction via the MAPK (mitogen-activated protein kinase) pathway and thereby cell proliferation [15]. In prostate cancer, HERV-K Env expression may be weak, presumably because of the predominant expression of env-deficient proviruses.…”